Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes

Abstract

There is compelling evidence that glial-immune interactions contribute to the progression of neurodegenerative diseases. The adaptive immune response has been implicated in disease processes of amyotrophic lateral sclerosis (ALS), but it remains unknown if innate immune signaling also contributes to ALS progression. Here we report that deficiency of the innate immune adaptor TIR domain-containing adaptor inducing interferon-β (TRIF), which is essential for certain Toll-like receptor (TLR) signaling cascades, significantly shortens survival time and accelerates disease progression of ALS mice. While myeloid differentiation factor 88 (MyD88) is also a crucial adaptor for most TLR signaling pathways, MyD88 deficiency had only a marginal impact on disease course. Moreover, TRIF deficiency reduced the number of natural killer (NK), NK-T-lymphocytes, and CD8-T cells infiltrating into the spinal cord of ALS mice, but experimental modulation of these populations did not substantially influence survival time. Instead, we found that aberrantly activated astrocytes expressing Mac2, p62, and apoptotic markers were accumulated in the lesions of TRIF-deficient ALS mice, and that the number of aberrantly activated astrocytes was negatively correlated with survival time. These findings suggest that TRIF pathway plays an important role in protecting a microenvironment surrounding motor neurons by eliminating aberrantly activated astrocytes.

Phenotypic heterogeneity of astrocytes in motor neuron disease

“…However, they are negative for CD68 and Iba‐1, typical microglial markers, concluding that these cells are aberrantly activated astrocytes (Fig. b) . As these cells do not express typical microglial markers, CD68 and Iba‐1, the origin and identity of these cells might be different from aberrant glia discussed in the prior section.…”

“…1b). 73 As these cells do not express typical microglial markers, CD68 and Iba-1, the origin and identity of these cells might be different from aberrant glia discussed in the prior section.…”

“…Although the phenotypic changes of reactive astrocytes and their characteristics were described, the fate of those activated astrocytes has not been shown. The authors recently uncovered the mechanism for eliminating overactivated astrocytes in SOD1‐ALS models . When TIR domain–containing adapter protein–inducing interferon‐β (TRIF), an innate immune adaptor protein essential for the Toll‐like receptor (TLR) 3/4 was deleted, disease progression was substantially accelerated, thereby shortening the survival time of SOD1 mice.…”

“…In Mac‐2 + astrocytes, accumulation of p62 and ubiquitin, as well as elevated expression of nicotinamide adenine dinucleotide phosphate oxidase, suggests that they are neurotoxic by overproducing reactive oxygen species. Correlation analysis in SOD1‐ALS mice showed that greater numbers of Mac‐2 + astrocytes predicted shorter survival times of ALS mice, suggesting that they are harmful to motor neurons . It is possible that the pathways other than TRIF signaling might participate in eliminating abnormal reactive astrocytes.…”

Neuroinflammation in dementia and neurodegeneration

“…Furthermore, they identified phenotypic heterogeneity in reactive astrocytes in ALS. They found toxic species of reactive astrocytes, known as aberrantly activated astrocytes, which contribute to accelerated disease progression in ALS rodent models . The surface marker expressions, ultrastructural studies and fate of those astrocytes are extensively reviewed.…”